Obesity and overweight is a major factor in the cause of high blood cholesterol and it is estimated that in the United States, roughly 300,000 deaths per year are directly related to obesity, and more than 80% of these deaths are in patients with a BMI over 30. For patients with a BMI over 40, life expectancy is reduced significantly (as much as 20 years for men and five years for women). Obesity also increases the risk of developing a number of chronic diseases, including: insulin resistance, type II diabetes, high blood pressure, high cholesterol, stroke, heart attacks, sleep apnea, congestive heart failure, osteoarthritis and cancer. In particular High levels of cholesterol have been associated with cardiovascular diseases as well as atherosclerosis.
There is currently only one pharmaceutical treatment for obesity: Orlistat, which is Food and Drug Administration (FDA) approved. Orlistat works by affecting the body's process of nutrient adsorption in the gastro intestinal (GI) tract, blocking fat digestion and lowering caloric absorption by inhibiting pancreatic lipases. An over the counter compound based on dietary fibers (for example, fermentable fibers based on pectin) has been additionally commercialized. Other compounds on the verge of approval are based on mechanisms of increased metabolism, or suppression of appetite. Drugs based on combination treatments have recently been suggested as suitable alternatives in improving the efficacy of pharmaceutical compounds based for weight loss. However several of those have had to be removed from the market due to the link with heart valve damage, for example fenfluramine and dexfenfluramine. Another example, Sibutramine has been withdrawn from the market in the United States, the UK, the EU, Australia, Canada, Hong Kong and Colombia. Sibutramine risks (non-life threatening myocardial infarction and stroke) outweigh the benefits of its use against obesity.
According to the World Health Organization (WHO) an 8.7% of the total burden of disease of the European Region can be addressed to high blood cholesterol. [Hockley T et al. European Cholesterol Guidelines report 2007] Furthermore, cholesterol reduction in patients with coronary disease retards or reverses the progression of atherosclerotic disease. [Garber A M et al. Ann Intern Med, 124:518-531, 1996] Statins are the most widely used lipid lowering drug used for prevention of coronary diseases in high risk patients although there are controversies regarding their positive effects in preventing death and cardiovascular diseases in low and moderate risk patients. [Tonelli M CMAJ 183:1189-1202, 2011; Ward S, Health Technol Assess. 11:1-160, 2007] There are alternatives to statins in the form of fibrates and resins, some of them are applied in combination with statin based therapies. It has been highlighted that lipid lowering treatments only have effectiveness in 51% of patients, after dietary recommendations and increased physical activity. [European Heart Journal, 22:554-572, 2001]. Furthermore, due to the large number of patients qualifying for statin based therapies, there is a large number of intolerant patients and patients with discomforts such as muscle complaints. The latter is the major symptom limiting the use of statins. [Marcini J et al. Canadian J of Cardiology, 27:635-662, 2011]. Hence, there is a need of new and more efficient lipid lowering treatment alternatives with and without the combination of lipid lowering drugs.
Silicon occurs naturally in nature as silicon dioxide (SiO2) or the corresponding silicic acids that result from the hydration of the oxide. Human serum contains 11-25 μg silicon/dL [EFSA Journal, 2009, 1132, 1-24] and remains relatively constant suggesting that it is rapidly distributed in the body and/or excreted. Absorbed silicon is mainly excreted via the urine without evidence of toxic accumulation in the body. [EFSA Journal, 2009; Reffit D M et al. J Inorg Biochem, 76:141-147, 1999] Hence, silicon content in the urine can be used as indicator for silicon absorption. [Reffit 1999, Jugdaohsingh R et al. Am J Clin Nutr, 75:887-893, 2002] Jugdaohsingh et al. showed that food-based silica is digested and absorbed from the gastrointestinal tract in humans. A mean of 40.9% of the ingested silicon was excreted within 6 h after intake with some variations depending on the silicon source, corresponding to 20 mg excreted silicon/day. [Jugdaohsingh 2002]
The intake of silica has already been proposed for lowering blood lipid or cholesterol levels e.g. in the form of: (a) fumed silica, (b) diatomaceous earth and (c) silica hydrogel:
(a) Studies performed in rats by Peluso et al. have shown that intake had a clear hypocholesterolemic effect on Cholesterol-Fed rats by reducing total levels of plasma cholesterol, with a decrease in both very-low density lipoprotein (VLDV), and low-density lipoprotein (LDL) cholesterol. [Peluso R M et al. J Nutr Met, 124:853-860, 1994] The intake of silicon dioxide in (a) was in the form of non-porous fumed silica (CAB-O-SIL® EH-5, typically with average size between 120 and 300 nm, and typically with BET surface area of approximately 380 m2/g). No changes in body weight were observed when comparing control animals to the animals receiving silicon dioxide. [Peluso R M et al. J Nutr Met, 124:853-860, 1994](b) Wachter et al. showed a lowering effect on blood cholesterol levels in humans after oral intake of diatomaceous earth. [Wachter H et al. Eur J Med Res, 3:211-215, 1998; EP 0778027 A2] Diatomaceous earth is a largely amorphous silica from sedimentary rock, used as dietary food additive for improving, e.g., the shape of nails, hairs and skin (approved by the U.S. FDA as food additive). Its intake reduced blood cholesterol as well as LDL cholesterol and triglycerides. No changes of body mass were observed. [Wachter 1998](c) Large pore size silica hydrogel containing about 50 to 80 weight-% water can reduce lipid or cholesterol blood levels in chicken fed on high fat diet. [U.S. Pat. No. 4,180,566 A] The silica hydrogel has no effect on body weight neither under standard nor high fat diet.
The blood lipid lowering effect in the above mentioned publications was majorly adjudicated to bile acid sequestration [as also described in U.S. Pat. No. 4,185,088 A] and elimination through the stools leading to increased production of bile acids from cholesterol in the organism. Neither body fat nor body weight lowering effects are observed in the above referred publications. Recently, ordered porous materials (e.g. silica) have been studied as carriers for the delivery of poorly water-soluble drugs and for controlled release of pharmaceutical compounds. [Salonen J, et al. J Control Release 108:362-374, 2005; Kaukonen A M, et al. Eur J Pharm Biopharm 66:348-356, 2007; Shen S.C International Publication Number WO 2010/050897 A1, and Garcia-Bennett et al. ChemMedChem, 43-48, 2012].
Ordered mesoporous materials exhibit a 2-dimensional (2-d) or 3-dimensional (3-d) ordered array of cylindrical or cage type pores (in the range of 2 to 50 nm) separated by thin silica walls. Bioactive drugs can be molecularly dispersed in these pores up to a certain loading. The influx diffusion of water to the pore surfaces provides for a rapid release of poorly water-soluble drugs if the drug compound is loaded in an amorphous state.
Ordered mesoporous materials have been attracting much attention because of the regular and adjustable pore size, different pore structures, high surface area and pore volume, high concentrations of silanol groups which ease their functionalization and conjugation to other chemical entities. They are particularly useful for the selective adsorption of different molecules due to their precise pore size distribution, and as such, are readily used in sensors and for specific adsorption of gases. Numerous syntheses have been reported for mesoporous materials based on the use of templates, or porogens, for the formation of ordered porosity. The most common preparations use surfactants as the templates, allowing tailoring porosities in the orders between 1.5 and 30 nm with good control over pore size distribution, pore structure and particle size. Examples of these materials include MCM-41, AMS-6, and SBA-15. Nanoporous folic acid materials (NFM-1) have been developed by using the non-surfactant folic acid as template. [Garcia-Bennett A E, International Publication Number WO 2009/101110 A2] These materials have the 2-D hexagonal pore structure with the pore size controllable in the range between 1.8 and 3.5 nm and varied morphologies.